RNA-binding proteins are essential for a wide variety of cellular and developmental functions. They participate in RNA processing, editing, transport, localization, stabilization, and the posttranscriptional control of mRNAs. The RNA binding activity of these proteins is mediated by specific RNA-binding domains contained within the proteins. A variety of conserved RNA binding motifs have been defined through comparisons of amino acid homologies and structural similarities within these RNA-binding domains. These motifs include the RNP motif, an arginine-rich motif, the zinc-finger motif, the Y-box, the KH motif, and the double-stranded RNA-binding domain (dsRBD), all of which are characterized by specific consensus sequences (Burd, C. G. and Dreyfuss, G. (1994) Science 265:615-621).
The double-stranded RNA-binding domain (dsRBD) exclusively binds double-stranded RNA or RNA-DNA. A dsRBD motif consists of a region of approximately 70 amino acids which includes basic residues and contains a conserved core sequence with a predicted .alpha.-helical structure. The dsRBD motif is found in at least 20 known or putative RNA-binding proteins from different organisms. There are two types of dsRBDs; Type A, which is homologous along its entire length with the defined consensus sequence, and Type B, which is more highly conserved at its C terminus than its N terminus. These domains have been functionally delineated in specific proteins by deletion analysis and RNA binding assays (St Johnston, D., et al. (1992) Proc. Natl. Acad. Sci. 89:10979-10983).
Double stranded RNA-binding proteins participate in posttranscriptional regulation pathways which control gene expression. Posttranscriptional regulation allows the modulation of protein expression in the absence of new transcription and is active during entry into the M phase of the cell cycle, in viral infections, and in stress and heat shock conditions. The human cellular TAR RNA binding proteins (TRBP and TRBP2), contain two dsRBDs and participate in the trans-activation of human immunodeficiency virus type-1 (HIV-1) genes. On integration into the host genome, HIV-1 remains latent until basal transcription produces a threshold level of the viral trans-activator protein, Tat. Tat increases the rate of viral mRNA production by increasing the elongation capacity of RNA polymerase. Tat interacts with the transcription machinery after binding to the trans-activation-responsive (TAR) RNA stem-loop element found at the 5 end of all HIV-1 transcripts. TRBP and TRBP2 proteins bind to TAR RNA with TAT and synergistically effect trans-activation. Biologically, TRBP has a growth-promoter effect and when overexpressed produces a transformed cell phenotype (Gatignol, A., et al. (1996) Gene Expression 5:217-228).
Gene expression is also down-regulated by dsRBDs, as has been shown with the mammalian double-stranded RNA-dependent protein kinase (PAR). PAR, which is a cell growth inhibitor, is activated by binding to double-stranded RNA or to single-stranded RNA with double-stranded regions (viral RNA or cellular RNA stem-loop structures). Activated PKR phosphorylates eukaryotic initiation factor eIF-2a inhibiting translation and preventing viral replication. The mouse Prbp protein, which contains two dsRBDs, affects the level of the Prm-1 gene by repressing its transcription and allowing normal spermatid differentiation (Benkirane, M. et al. (1997) EMBO J. 16: 611-624; Lee, K. et al. (1999) Mol. Cell. Biol. 16:3023-3034).
The discovery of a double-stranded RNA-binding protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and disorders of cell growth.